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EDITORIAL
Evaluating Typhoid Vaccine Effectiveness in Travelers’ Vaccination Conall H. Watson, MRPharmS, MFPH Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK DOI: 10.1111/jtm.12185
This Editorial refers to the article by Wagner et al., pp. 87–93 of this issue.
T
yphoid fever exists somewhere in the borderlines of the neglected tropical diseases. Its history in Europe and North America, and market for vaccination of travelers, means that typhoid is not entirely in the pharmaceutical public health wilderness. Travel immunization recommendations, however, are based on the results of efficacy trials performed in typhoid-prone areas, rather than on the evidence of direct effectiveness in people journeying from low-risk settings. Two recent epidemiological studies address vaccine effectiveness in travelers,1,2 one of which is in this issue of JTM. In that study, Wagner and colleagues used the detailed enteric fever surveillance records of the English public health services to compare typhoid Vi-polysaccharide (ViPS) vaccine history among typhoid and paratyphoid cases.2 They estimated that vaccine effectiveness against typhoid was 65% over 3 years in travelers, after multivariable adjustment, consistent with efficacy trials. Their approach, using the indirect cohort design or “Broome method,” first developed to examine pneumococcal vaccine efficacy across different serotypes,3 is well suited to the question. Paratyphoid cases are suitable controls for typhoid because the geographies in which they arise and the routes of acquisition are similar. Crucially, ViPS vaccine does not protect against paratyphoid: for unbiased estimates of typhoid vaccine effectiveness, it is necessary to have equal probability of paratyphoid fever notification in ViPS-vaccinated and -unvaccinated groups.4 There is as yet no licensed vaccine against Salmonella Paratyphi although a number of vaccines are in development,5 and Ty21a oral typhoid vaccines, which have possible cross protection with S. Paratyphi A and B,6 are uncommonly prescribed in the UK and do not feature in the analysis. Similar indirect cohort studies of forthcoming typhoid Corresponding Author: Conall H. Watson, MRPharmS, MFPH, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. E-mail: [email protected] © 2015 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015; Volume 22 (Issue 2): 76–77
Vi-conjugate vaccines may be possible if there is an interval between the widespread adoption of these and any future paratyphoid vaccines, or with detailed vaccine history-taking. The suitability of paratyphoid controls bears further consideration: if the likelihood of pre-travel vaccination was different between the cohorts who ultimately end up as paratyphoid and typhoid patients, then this could also bias the estimates.7 For example, travelers visiting friends and relatives may be less likely to seek advice or be vaccinated against typhoid than holidaymakers,8 and they may also have different Salmonella enterica serovar exposure. Case–control studies in urban Asian settings have suggested different risk factors for the two pathogens. In Jakarta, Indonesia, typhoid risk factors were characterized as “within the household”: recent typhoid cases, shared plates, and the absence of soap or toilets.9 Paratyphoid was associated with extra-household factors: eating street food or recent flooding. In Kathmandu, Nepal, a similar categorization might be inferred: street-food consumption and migration were associated with paratyphoid fever, in contrast to typhoid for which risk factors were poor water and low income.10 So, there might be some differences in enteric fever case cohorts in terms of backpackers and sunseekers eating out and travelers staying with family and friends. This seems borne out to a modest extent in this study, with tourists making a slightly higher proportion of the paratyphoid group, which also has a higher mean age, though there was minimal difference in effect size after adjustment for age group, sex, country of birth, and ethnicity. Particular strengths of Wagner’s paper are the comprehensive breakdown by traveler subgroup and by time and the validation of vaccine histories by cross-checking a subset of enteric fever notifications with the patients’ primary care records. One subgroup finding of interest is the possibility that vaccine efficacy may be reduced for travelers of white ethnicity, though low numbers make estimates imprecise and no significant difference was
77
Measuring Typhoid Vaccine Effectiveness
described. While genetic differences in typhoid susceptibility have been demonstrated elsewhere,11 it would be premature to suggest that this arises in UK travelers. Given the comprehensiveness of enteric fever surveillance in England, confirmation or refutation may be possible as more data accumulate. Further years’ data could also determine if reduced-antigen Typhim ViPS batches, withdrawn by Sanofi Pasteur MSD from the UK, show impaired efficacy with time. It is reassuring that the first year of protection shows no difference from that of the full-potency batches. A similar indirect cohort study using paratyphoid controls was also completed recently by the US Centers for Disease Control and Prevention (CDC). Due to missing data, this study assessed efficacy across both ViPS and Ty21a vaccines and had less complete vaccine history ascertainment than that in England. The CDC found 80% vaccine effectiveness, higher than that in trials, which they ascribe to less intense exposure among American travelers compared with residents of typhoid-endemic study sites, both in ingested dose and time at risk.1 High infectious doses of S. Typhi can overcome vaccine-derived immunity12 (S. Paratyphi is thought to require higher infectious doses than S. Typhi, with food being a multiplier, contributing to the differential epidemiology9,10 ), while in one Australian study, all enteric fever patients had been abroad for at least 3 weeks.13 As well as measuring vaccine effectiveness within their own travelers, the two effectiveness studies provide ecological indicators of the effect of vaccine coverage on typhoid cases averted, adding to previous reports.14 In the United States, where just 8% of the notional cohort was vaccinated, the ratio was around 4 typhoid cases to each paratyphoid case, whereas in England, where 29% of the studied enteric fever patients had been vaccinated, the case ratio was closer to 1:1. Some of the difference in vaccine uptake may be due to typhoid vaccination being offered free-of-charge to travelers on the English National Health Service, as a public health measure intended to provide indirect protection to the families and communities of travelers, as well as direct protection to those receiving vaccines. The limited vaccine uptake among English travelers at risk of typhoid suggests that, on its own, removing financial barriers to access is not sufficient for all such voyagers to receive predeparture vaccination, with opportunistic pre-travel advice from family physicians being one option suggested for improving uptake among travelers of south Asian ethnicity.8 It also serves to remind us that while we await the arrival of paratyphoid vaccines and Vi-conjugate vaccines, the success of these interventions depends not just on their efficacy, but on the ability of public health systems to deliver vaccines to people who need them, whether residents of endemic areas or their visitors.
Acknowledgment C. H. W. is supported by the UK Medical Research Council, grant MR/J003999/1. Declaration of Interests The author had travel and accommodation paid for by the Coalition against Typhoid to attend a typhoid vaccine modeling premeeting and the 8th International Conference on Typhoid Fever and Other Invasive Salmonelloses, in Dhaka, Bangladesh, 2013. References 1. Mahon BE, Newton AE, Mintz ED. Effectiveness of typhoid vaccination in US travelers. Vaccine 2014; 32:3577–3579. 2. Wagner K, Freedman J, Andrews N, Jones J. Effectiveness of the typhoid Vi vaccine in overseas travellers from England. J Travel Med 2014; 22:87–93. 3. Broome CV, Facklam RR, Fraser DW. Pneumococcal disease after pneumococcal vaccination. N Engl J Med 1980; 303:549–552. 4. Andrews N, Waight PA, Borrow R, et al. Using the indirect cohort design to estimate the effectiveness of the seven valent pneumococcal conjugate vaccine in England and Wales. PLoS ONE 2011; 6:e28435. 5. Martin LB. Vaccines for typhoid fever and other salmonelloses. Curr Opin Infect Dis 2012; 25:489–499. 6. Pakkanen SH, Kantele JM, Kantele A. Cross-reactive gut-directed immune response against Salmonella enterica serovar Paratyphi A and B in typhoid fever and after oral Ty21a typhoid vaccination. Vaccine 2012; 30:6047–6053. 7. Rodrigues LC, Smith PG. Use of the case–control approach in vaccine evaluation: efficacy and adverse effects. Epidemiol Rev 1999; 21:56–72. 8. Baggett HC, Graham S, Kozarsky PE, et al. Pretravel health preparation among US residents traveling to India to VFRs: importance of ethnicity in defining VFRs. J Travel Med 2009; 16:112–118. 9. Vollaard AM, Ali S, van Asten H, et al. Risk factors for typhoid and paratyphoid fever in Jakarta, Indonesia. JAMA 2004; 291:2607–2615. 10. Karkey A, Thompson CN, Tran N, et al. Differential epidemiology of Salmonella typhi and Paratyphi A in Kathmandu, Nepal: a matched case control investigation in a highly endemic enteric fever setting. PLoS Negl Trop Dis 2013; 7:e2391. 11. Dunstan SJ, Hue NT, Han B, et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet 2014; 46:1333–1336. 12. Waddington CS, Darton TC, Woodward WE, et al. Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. J Infect 2014; 68:405–418. 13. Blackstock SJ, Sheppeard VK, Paterson JM, Ralph AP. Typhoid and paratyphoid fever in Western Sydney Local Health District, NSW, January-June 2011. N S W Public Health Bull 2013; 23:148–152. 14. Connor BA, Schwartz E. Typhoid and paratyphoid fever in travellers. Lancet Infect Dis 2005; 5:623–628.
J Travel Med 2015; 22: 76–77
EDITORIAL
Evaluating Typhoid Vaccine Effectiveness in Travelers’ Vaccination Conall H. Watson, MRPharmS, MFPH Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK DOI: 10.1111/jtm.12185
This Editorial refers to the article by Wagner et al., pp. 87–93 of this issue.
T
yphoid fever exists somewhere in the borderlines of the neglected tropical diseases. Its history in Europe and North America, and market for vaccination of travelers, means that typhoid is not entirely in the pharmaceutical public health wilderness. Travel immunization recommendations, however, are based on the results of efficacy trials performed in typhoid-prone areas, rather than on the evidence of direct effectiveness in people journeying from low-risk settings. Two recent epidemiological studies address vaccine effectiveness in travelers,1,2 one of which is in this issue of JTM. In that study, Wagner and colleagues used the detailed enteric fever surveillance records of the English public health services to compare typhoid Vi-polysaccharide (ViPS) vaccine history among typhoid and paratyphoid cases.2 They estimated that vaccine effectiveness against typhoid was 65% over 3 years in travelers, after multivariable adjustment, consistent with efficacy trials. Their approach, using the indirect cohort design or “Broome method,” first developed to examine pneumococcal vaccine efficacy across different serotypes,3 is well suited to the question. Paratyphoid cases are suitable controls for typhoid because the geographies in which they arise and the routes of acquisition are similar. Crucially, ViPS vaccine does not protect against paratyphoid: for unbiased estimates of typhoid vaccine effectiveness, it is necessary to have equal probability of paratyphoid fever notification in ViPS-vaccinated and -unvaccinated groups.4 There is as yet no licensed vaccine against Salmonella Paratyphi although a number of vaccines are in development,5 and Ty21a oral typhoid vaccines, which have possible cross protection with S. Paratyphi A and B,6 are uncommonly prescribed in the UK and do not feature in the analysis. Similar indirect cohort studies of forthcoming typhoid Corresponding Author: Conall H. Watson, MRPharmS, MFPH, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. E-mail: [email protected] © 2015 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015; Volume 22 (Issue 2): 76–77
Vi-conjugate vaccines may be possible if there is an interval between the widespread adoption of these and any future paratyphoid vaccines, or with detailed vaccine history-taking. The suitability of paratyphoid controls bears further consideration: if the likelihood of pre-travel vaccination was different between the cohorts who ultimately end up as paratyphoid and typhoid patients, then this could also bias the estimates.7 For example, travelers visiting friends and relatives may be less likely to seek advice or be vaccinated against typhoid than holidaymakers,8 and they may also have different Salmonella enterica serovar exposure. Case–control studies in urban Asian settings have suggested different risk factors for the two pathogens. In Jakarta, Indonesia, typhoid risk factors were characterized as “within the household”: recent typhoid cases, shared plates, and the absence of soap or toilets.9 Paratyphoid was associated with extra-household factors: eating street food or recent flooding. In Kathmandu, Nepal, a similar categorization might be inferred: street-food consumption and migration were associated with paratyphoid fever, in contrast to typhoid for which risk factors were poor water and low income.10 So, there might be some differences in enteric fever case cohorts in terms of backpackers and sunseekers eating out and travelers staying with family and friends. This seems borne out to a modest extent in this study, with tourists making a slightly higher proportion of the paratyphoid group, which also has a higher mean age, though there was minimal difference in effect size after adjustment for age group, sex, country of birth, and ethnicity. Particular strengths of Wagner’s paper are the comprehensive breakdown by traveler subgroup and by time and the validation of vaccine histories by cross-checking a subset of enteric fever notifications with the patients’ primary care records. One subgroup finding of interest is the possibility that vaccine efficacy may be reduced for travelers of white ethnicity, though low numbers make estimates imprecise and no significant difference was
77
Measuring Typhoid Vaccine Effectiveness
described. While genetic differences in typhoid susceptibility have been demonstrated elsewhere,11 it would be premature to suggest that this arises in UK travelers. Given the comprehensiveness of enteric fever surveillance in England, confirmation or refutation may be possible as more data accumulate. Further years’ data could also determine if reduced-antigen Typhim ViPS batches, withdrawn by Sanofi Pasteur MSD from the UK, show impaired efficacy with time. It is reassuring that the first year of protection shows no difference from that of the full-potency batches. A similar indirect cohort study using paratyphoid controls was also completed recently by the US Centers for Disease Control and Prevention (CDC). Due to missing data, this study assessed efficacy across both ViPS and Ty21a vaccines and had less complete vaccine history ascertainment than that in England. The CDC found 80% vaccine effectiveness, higher than that in trials, which they ascribe to less intense exposure among American travelers compared with residents of typhoid-endemic study sites, both in ingested dose and time at risk.1 High infectious doses of S. Typhi can overcome vaccine-derived immunity12 (S. Paratyphi is thought to require higher infectious doses than S. Typhi, with food being a multiplier, contributing to the differential epidemiology9,10 ), while in one Australian study, all enteric fever patients had been abroad for at least 3 weeks.13 As well as measuring vaccine effectiveness within their own travelers, the two effectiveness studies provide ecological indicators of the effect of vaccine coverage on typhoid cases averted, adding to previous reports.14 In the United States, where just 8% of the notional cohort was vaccinated, the ratio was around 4 typhoid cases to each paratyphoid case, whereas in England, where 29% of the studied enteric fever patients had been vaccinated, the case ratio was closer to 1:1. Some of the difference in vaccine uptake may be due to typhoid vaccination being offered free-of-charge to travelers on the English National Health Service, as a public health measure intended to provide indirect protection to the families and communities of travelers, as well as direct protection to those receiving vaccines. The limited vaccine uptake among English travelers at risk of typhoid suggests that, on its own, removing financial barriers to access is not sufficient for all such voyagers to receive predeparture vaccination, with opportunistic pre-travel advice from family physicians being one option suggested for improving uptake among travelers of south Asian ethnicity.8 It also serves to remind us that while we await the arrival of paratyphoid vaccines and Vi-conjugate vaccines, the success of these interventions depends not just on their efficacy, but on the ability of public health systems to deliver vaccines to people who need them, whether residents of endemic areas or their visitors.
Acknowledgment C. H. W. is supported by the UK Medical Research Council, grant MR/J003999/1. Declaration of Interests The author had travel and accommodation paid for by the Coalition against Typhoid to attend a typhoid vaccine modeling premeeting and the 8th International Conference on Typhoid Fever and Other Invasive Salmonelloses, in Dhaka, Bangladesh, 2013. References 1. Mahon BE, Newton AE, Mintz ED. Effectiveness of typhoid vaccination in US travelers. Vaccine 2014; 32:3577–3579. 2. Wagner K, Freedman J, Andrews N, Jones J. Effectiveness of the typhoid Vi vaccine in overseas travellers from England. J Travel Med 2014; 22:87–93. 3. Broome CV, Facklam RR, Fraser DW. Pneumococcal disease after pneumococcal vaccination. N Engl J Med 1980; 303:549–552. 4. Andrews N, Waight PA, Borrow R, et al. Using the indirect cohort design to estimate the effectiveness of the seven valent pneumococcal conjugate vaccine in England and Wales. PLoS ONE 2011; 6:e28435. 5. Martin LB. Vaccines for typhoid fever and other salmonelloses. Curr Opin Infect Dis 2012; 25:489–499. 6. Pakkanen SH, Kantele JM, Kantele A. Cross-reactive gut-directed immune response against Salmonella enterica serovar Paratyphi A and B in typhoid fever and after oral Ty21a typhoid vaccination. Vaccine 2012; 30:6047–6053. 7. Rodrigues LC, Smith PG. Use of the case–control approach in vaccine evaluation: efficacy and adverse effects. Epidemiol Rev 1999; 21:56–72. 8. Baggett HC, Graham S, Kozarsky PE, et al. Pretravel health preparation among US residents traveling to India to VFRs: importance of ethnicity in defining VFRs. J Travel Med 2009; 16:112–118. 9. Vollaard AM, Ali S, van Asten H, et al. Risk factors for typhoid and paratyphoid fever in Jakarta, Indonesia. JAMA 2004; 291:2607–2615. 10. Karkey A, Thompson CN, Tran N, et al. Differential epidemiology of Salmonella typhi and Paratyphi A in Kathmandu, Nepal: a matched case control investigation in a highly endemic enteric fever setting. PLoS Negl Trop Dis 2013; 7:e2391. 11. Dunstan SJ, Hue NT, Han B, et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet 2014; 46:1333–1336. 12. Waddington CS, Darton TC, Woodward WE, et al. Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. J Infect 2014; 68:405–418. 13. Blackstock SJ, Sheppeard VK, Paterson JM, Ralph AP. Typhoid and paratyphoid fever in Western Sydney Local Health District, NSW, January-June 2011. N S W Public Health Bull 2013; 23:148–152. 14. Connor BA, Schwartz E. Typhoid and paratyphoid fever in travellers. Lancet Infect Dis 2005; 5:623–628.
J Travel Med 2015; 22: 76–77
